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Antiviral and antiretroviral drugs
Lecture Details Liz Davis; Week 12 MED1011; Lecture Content DNA viruses include adenoviruses, hepadnaviruses, herpes viruses, papillomavirus; RNA viruses are orthomyxoviruses, paramyxoviruses, retroviruses. Currently available drugs are virustatic, only affects actively replicating forms, host immunocompetence important, usefulness may be limited by resistance development. Most viral diseases are self limiting and don't require therapy. Targets include attachment and entry into host cell, viral uncoating, viral genome replication, viral particle assembly, release of viral progeny. Difficult to predict therapeutic efficiency from in vitro studies. Guanine analogs include aciclovir used for herpes simplex, shingles. They are incorporated into DNA chain and terminate elongation. Converted to triphosphates by thymidine kinase. Used orally, IV or topically; poor gut absorption, poor skin absorption, generally well tolerated, safe to used in pregnancy, renal dysfunction and neurotoxicity. Contraindications are renal impairment, drug sensitivity. Aciclovir, valaciclovir, famiciclovir are all used for shingles, HSV, ganiciclovir, valganciclovir are for CMV. Non-nucleoside DNA polymerase inhibitors for example foscarnet, used for severe HSV and CMV infection where there may be resistance to aciclovir. Does not need to be activated by thymidine kindase. Has less selectivity than aciclovir. Neuraminidase inihibitors eg oseltamivir, used for influenza A and B, inhibits release of progeny from cell. Inhibition means virus remains attached. Selectivity due to oseltamivir being competitive, antagonist of flu A and B neuraminidase; given orally. It undergoes liver metabolism and is widely distributed. Is well tolerated. Inhibitor of viral gene uncoating are amantadine used for influenza A. Blocks ion channel protein in viral envelope, prevents H influx which is essential for RNA release from nucleoprotein complex. It is orally active, high lipophilicity, large Vd, renal and tubular excretion. Adverse effects are frequent and dose related. 50% develop livedo reticularis. Interferon alfa binds to cell surface receptors and initiates production of enzymes that inhibit translation of viral mRNA to protein, inhibits viral proliferation. Enhances phagocytosis of viruses and induces apoptosis of affected cells. Given IV/IM, short half life, pegylation increases t1/2. Used for chronic hep B or C. Antiretroviral therapy is preferred in combination, HAART. High adverse effect rate. Treatment can be individualised. It can also reduce transmission. Targets are entry into host cell, reverse transcriptase enzyme, viral maturation. Nucleoside reverse transcriptase inhibitors (zidovudine) require activation (conversion to TP); are incorporated into the DNA chain and terminates chain elongation, is a competitive inhibitor. It has selectivity for viral reverse transcriptase. Zidovudine is anti HIV, it prolongs life and decreases mother-baby transmission, orally active or given IV, resistance develops rapidly. Non-nucleoside reverse transcriptase inhibitors (nevirapine) prevents mother-baby transmission of HIV, binds and denatures reverse transcriptase enzyme, has drug interacitons with liver CYP-450 enzyme. Has less serious adverse effects and resistance develops rapidly. Protease inhbitors (ritonavir) lead to release of immature virus particles. They suffer from serious adverse effects (GI effects, hepatotoxicity, drug interactions). Inhibition of fusion with host cells (enfurvitide), binds to viral glycoprotein subunit gp41 and prevents fusion of HIV envelope and CD4 receptor of host cell. Is used in HIV treatment when other treatments have failed. Inhibitors of viral integrase (raltegravir) interferes with viral DNA replication and translation by inhibiting integration into host DNA. Used with at least 2 active antiretrovirals. Readings Rang 47=